Pharmacological Targeting of Endothelial Dysfunction in Atherogenesis Cardiovascular disease is the leading cause of morbidity and mortality in the United States and is an emerging epidemic world-wide. In particular, atherosclerosis is a life-threatening disease strongly associated with risk factors such as elevated cholesterol levels, high blood pressure and diabetes. There are effective commercially available therapeutics that target these systemic risk factors. However, despite these advances, there is still a significant rate of adverse events in patients prescribed these therapeutics and a significant population that suffer adverse cardiovascular events in the absence of these conventional systemic risk factors. Importantly, in the face of potent systemic classical cardiovascular risk factors, certain regions of the arterial vasculature remain relatively resistant to the development of atherosclerotic lesions while some are relatively susceptible. Interestingly, the anatomical locations of these protected and susceptible regions are predictable between individuals and even between species. Multiple lines of evidence suggest that the specific hemodynamic conditions within these arterial regions exert a protective influence on the local vascular endothelium, and thus inhibit early lesion development. In contrast, hemodynamic conditions present in other regions of the vasculature evoke a pro-inflammatory pro-atherogenic dysfunctional state in the endothelium. Despite recent progress in the understanding of some of the biological mechanisms responsible for hemodynamics-induced atheroprotection and atherosusceptibility, these basic discoveries have not yet been translated into therapeutic strategies for the treatment of cardiovascular disease. In this project, the insights recently gained into the mechanisms underlying endothelial responses to hemodynamic flow will be used to establish a novel cardiovascular drug discovery platform. The major goals are to 1) discover small molecules able to induce the expression of atheroprotective genes in the context of pathological hemodynamic conditions, 2) identify potential drug targets that are critical for hemodynamics-induced atherosusceptibility, and 3) validate the effectiveness of using small molecules to improve endothelial function using several in vitro models of endothelial activation and inflammation. The knowledge generated by this project should establish a novel cardiovascular drug discovery effort targeting endothelial dysfunction, an unexplored but critical local risk factor for atherosclerosis.